Advances in molecular genetics will soon allow presymptomatic diagnosis of (or determination of increased genetic risk for) a large number of neuropsychiatric disorders. Such testing will enable researchers to study the evolution of disease in those determined to be at high genetic risk. More importantly, presymptomatic detection of disease will guide treatment, early intervention and prevention efforts. A-research program on testing for Huntington's disease (HD) using linked DNA markers was established at Johns Hopkins University in September 1986. The purpose of this research has been to determine: 1) the psychological and social consequences of presymptomatic diagnosis, 2) whether pre-testing characteristics can predict those consequences in individual cases, and 3) whether pre-testing education and counseling and post-test clinical follow- up can prevent or palliate morbid responses. To date, 38 healthy people at risk for HD have had informative predictive tests, and another 41 who want genetic testing are in the protocol. In the proposed continuation of this program, we will greatly increase the subject sample. We will enroll 150 new at-risk subjects and continue to evaluate all subjects tested (as well as those with uninformative tests and those who are non-tested controls) at regular intervals after testing to discover the psychological responses to knowledge of one's genetic status. We predict that: 1) those who test positive for the marker will, as a group, be slightly more distressed after testing than those who test negative, but will remain within normal limits on psychological tests and psychiatric interviews, and 2) social variables, personality characteristics, and psychological distress prior to genetic testing will be predictive of psychological and social outcome. Most of those who test positive for the genetic marker, and an individually-matched sample of those who test negative, will have semi-annual neurological, psychiatric, and neuropsychological evaluations, as well as annual MRI scans for quantitative brain volumetric studies and 18F-2-deoxyglucose PET scans for assessment of changes in regional brain metabolism. Using these techniques, we hope to be able to document the very earliest manifestations of disease onset. The hypothesis to be tested is that those who test positive for the marker will display morphologic changes in the caudate on MRI and reduced striatal glucose metabolism on PET prior to the emergence at risk for HD to determine the magnitude of the demand for presymptomatic testing and the variables that determine whether people risk for other neuropsychiatric disorders will seek predictive DNA testing.